Novel hypoglycemic agents



' cyclo [2.2. l ]hept-5-ene-2-ylmethyl, bicyclo[2.2.1]hept 2- United States Patent 3,305,556 NOVEL HYPOGLYCEMIC AGENTS James M. McManus, Uncasville, William M. McLamore,

Groton, and Gerald D. Laubach, Lyme, Conn., assignors to Chas. Pfizer & Co., Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Nov. 23, 1962, Ser. No. 239,809 13 Claims. (Cl. 260-2934) This application is a continuation-in-part of our copending application Serial No. 202,711 filed June 15, 1962, and now abandoned.

This invention relates to new and useful sulfamylureas which are effective in lowering the amount of sugar in the blood. More particularly, it is concerned with various novel cyclicsulfamylureas and with the acid and base salts thereof, as well as with the method of reducing the blood sugars in a diabetic subject by the oral administration thereto of said sulfamylureas or of one of their pharmaceutically acceptable salts.

The novel compounds which are included within the scope of the present invention are all selected from the group consisting of A. Those of the formula ZSO NHCONHR"' wherein (a) R' is a member selected from the group consisting alkyl having two to about eight carbon atoms, bi-

ylmethyl, polyfluoroalkyl, cycloalkyl-alkyl having from four to about nine carbon atoms, cycloalkyl having from three to about ten carbon atoms, including terpene-like radicals such as bornyl, aralkyl having from seven to about thirteen carbon atoms, p-chlorophenyl, p-di(lower alkyl) aminophenyl and S-(lower alkyl)mercaptophenyl; and

(b) Z represents a radical selected from the group consisting of wherein R is a member chosen from the group consisting of hydrogen, lower alkyl, trifluoroethyl, lower alkenyl, cycloalkyl and cycloalkenyl each containing up to six carbon atoms; 45

R is a member chosen from the group consisting of lower alkoxy, lower alkoxy-lower alkoxy, lower alkenyllower alkoxy, lower polyfluoroalkoxy and cycloalkoxy containing up to six carbon atoms; and when R and R are taken together with the common carbon atom, a r heterocyclic ring having from three to five carbon atoms wherein the hetero element is chosen from the group consisting of oxygen, sulfur and nitrogen;

0 R wherein R is lower alkyl; (3)

wherein X is a member chosen from the group consisting of oxygen, sulfur, l-oxosulfur and 1,1-dioxosulfur, and m is an integer of from four to five;

3,305,556 Patented Feb. 21, 1967 wherein R and R are each lower alkyl, and x is an integer from one to two; and

B. The alkali metal salts of A,

C. The alkaline earth metal salts of A,

D. The ammonium addition salts of A,

E. The amine addition salts of A, and

F. The acid addition salts of A wherein R (lower alkyl)aminophenyl.

Some logical subgeneric groups under the broad invention are:

(a) The compounds of A wherein Z is radical (1), including the salts of B through F;

(b) The compounds of A wherein Z is radical (2), including the salts of B through F;

(c) The compounds of A wherein Z is radical (3), including the salts of B through F; and

(d) The compounds of A wherein Z is radical (4), including the salts of B through F;

(e) The compounds of A wherein Z is radical (5), including the salts of B through F; and

(f) The compounds of A wherein Z is radical (6), including the salts of B through F.

Among the typical member compounds of this series are such novel cyclicsulfamylureas as l-[N-(4-methoxypiperidine)sulfonyl]-3-cyclohexylurea, 1-[N-(4-methoxy- 4 methylpiperidine)sulfonyl] 3-cycloheptylurea, l-[N- (3-methoxypiperidine)sulfonyl] 3 cyclohexylurea, 1- [N-(l-oxa-8-azaspiro[4.5]decane) sulfonyl]-3-cyclohexylurea, 1-[N-(2,2 pentamethylenemorpholine)sulfonyl]- 3-cycloheptylurea, 1-[N-(2,2-tetramethylenethiamorpholine)sulfonyl] 3 cyclopentylurea, 1-[N-(4,4-ethylenedioxypiperidine)sulfonyl] 3-cyclohexylurea, 1-[N-(4,4- ethylenedioxypiperidine) sulfonyl] 3-(bicyclo[2.2. l]hept- 5-ene-2-ylmethyl)-urea, and the like. Additionally, compounds in which the hydrogen atom of the NHR"' group is replaced by another member meeting the definition of R come within the scope of this invention. Further, compounds where Z is a fused bicyclic nitrogen-containing heterocyclic ring system such as tropane are also useful.

The new cyclicsulfamylurea compounds of this invention are especially valuable and useful as agents for lowering blood sugar levels when administered orally to an animal subject, including man. The advantages offered by the phannacologically acceptable compound of this invention are manifold: for instance, (1) they may be administered orally as aforesaid, thereby eliminating parenteral administration which is often very painful and irritating; (2) they lower 'blood sugar levels for a sustained period of time; (3) toxic side effects have been found to be either minimal or else completely absent; (4)

is p-di pharmacological investigation reveals no evidence of kidney damage or crystalluria; (5) they are easily prepared in good yield from readily available starting materials and lastly, (6) these compounds readily lend themselves to the preparation of suitable oral dosage formulations.

The herein described new compounds can be readily synthesized by the reaction of a cyclicaminosulfonylisocyanate with the appropriate amine or conversely, the reaction of a cyclicaminosulfonamide with the appropriate isocyanate or with compounds which can be converted into such an isocyanate during the course of the reaction; or the reaction of a cyclicaminosulfonylurethane with the appropriate amine or conversely, the reaction of a cyclicaminosulfonamide with an appropriate urethane; or the reaction of a cyclicaminosulfonamide with the appropriate N-monosubstituted carbamyl chloride or the conversion of a cyclicaminosulfonylurea to the desired 3-substituted compound by means of the appropriate amine; or the reaction of a cyclicaminosulfonamide with the appropriate 1,3-(disubstituted)urea; or the reaction of a cyclicaminosulfonyl chloride with the corresponding isourea in the form of a suitable salt, followed by acid hydrolysis of the resulting intermediate; or the reaction of a cyclicaminosulf-onyl chloride with the appropriate 1,3-(disubstituted)- thiourea or the corresponding substituted guanidine by either first desulfurizing or hydrolyzing these reagents or by employing them as such, followed by respective desulfurization or hydrolyzation to the desired cyclicsulfamylurea compound.

Preferred synthetic routes in this connection include the reaction of the cyclicaminosulfonamide with the appropriate isocyanate in accordance with a modification of the procedure of F. Kurzer [Journal of the Chemical Society (London), 1951, p. 1258], employing a strongly basic organic amine such as triethyl amine as a catalyst. Another preferred method of synthesis, which is even more desirable from the standpoint of yields, involves the reaction of an alkali metal or alkaline-earth metal salt of the cyclicaminosulfonamide with either a 1,1,3-trisubstituted urea such as (R") NCONHR' or with an aryl N- monosubstituted carbamate or a corresponding thiolcarbamate such as R"" XCONHR', where X is either oxygen or sulfur and R"" is an aryl group such as phenyl, pchlorophenyl, p-bromophenyl, p-nitrophenyl, p-acetylaminophenyl, p-tolyl, p-anisyl, a-naphthyl, S-napthyl, and the like.

The preferred methods of synthesis are illustrated below by the following two equations wherein M represents the cation of an alkali metal salt and X is either oxygen or sulfur as aforesaid:

Z-SO NHCONHR+R"XM This reaction is preferably carried out in the presence of a reaction-inert polar organic solvent medium. Typical organic solvents useful in this connection include the N,N-di(lower-alkyl) substituted derivatives of lower aliphatic hydrocarbon carboxamides such as dimethylformamide, dimethylacetamide, diethylformamide, diethylacetamide, as well as lower dialkyl sulfoxides and sulfones such as dimethyl sulfoxide, diethyl sulfoxide, diisopropyl sulfoxide, di-n-propyl sulfoxide, dimethylsulfone, diethyl sulfone, diisopropyl sulfone and di-n-propyl sulfone. It is desirable that the aforementioned solvent be present in sufiicient amount to dissolve each of the starting materials. In general, the reaction is conducted at a temperature that is in the range of from about C. up to about 150 C. for a period of about one-half to about ten hours. Recovery of the desired product from the reaction mixture is then most conveniently accomplished by first diluting the reaction solution with water and then adjusting the resulting aqueous solution to at least pH 8.0, followed by subsequent extraction of the basic aqueous solution with any water-immiscible organic solvent in order to remove minor amounts of unreacted or excess starting material that might possibly be present at this stage. Isolation of the desired cyclicsulfamylurea from the basic aqueous layer is then effected by the addition thereto of a dilute aqueous acid solution, wherein the acid is present in sufiicient amount to cause precipitation of said sulfamylurea to occur from solution.

In connection with a more detailed consideration of this preferred method of synthesis, the relative amounts of the agents employed is such that the molar ratio of the cyclicaminosulfonamide salt to either the 1,1-diaryl-3- (monosubstituted)urea or aryl N-monosubstituted carbamate or thiolcarbamate is desirably in the preferred range of from about 1:1 toabout 1:3, although substantially equimolar ratios will afford satisfactory results in this reaction. Nevertheless, an excess of the trisubstituted urea or aryl N-monosubstituted carbamate or thiolcarbamate is usually employed inasmuch as this not only aids in shifting the reaction equilibrium to the product side of the equation, but it is also advantageous in that the excess reagent is easily removed after completion of the reaction by means of the solvent extraction step previously referred to. Moreover, it is to be noted that the formation of the phenolic or aryl mercaptan by-products is greatly enhanced by the over-all basic character of the reaction mixture.

The principal starting materials necessary for the process of this invention are compounds which are either commercially available and/or are well-known in the prior art or else they are easily prepared in accordance with standard organic procedures previously described in the chemical literature and hence, well-known to those skilled in the art.

The other major starting materials required for this reaction, viZ., the 1,l-diaryl-3-(monosubstituted)ureas and the aryl N-monosubstituted carbamates or thiolcarbamates, are all readily prepared from common organic reagents by employing standard procedures well-known in the art. For instance, the desired trisubstituted urea may be prepared in accordance with the general procedure described by Reudel in the Recueil des Travaux Chimiques des Pays-Bas, vol. 33, p. 64 (1914), which is illustrated below by the following equation wherein R"" is the aryl group previously defined:

In the case of the aryl N-monosubstituted carbamate or thiolcarbamate type compounds, application of the wellknown Schotten-Baumann technique is extremely suitable.

Insofar as some of the cyclicsulfamylureas of this invention are amphoteric compounds, they are capable of forming a wide variety of salts with various acids and bases. In practice, it is preferable to employ a strong acid or base for such purposes in view of the nature of the compound which is to be reacted. Alhough such salts must be pharmaceutically acceptable as the final products are solely intended for oral human consumption, it is possible to first isolate the desired sulfamylurea from the reaction mixture in the form of a pharmaceutically unacceptable salt and then subsequently convert the latter salt to the free amphoteric compound by treatment with either acid or base as the case may be; the free cyclicsulfamylureas so obtained are then converted to a pharmaceutically acceptable salt thereof in the manner hereinafter indicated.

For instance, the acid and base salts of the sulfamylureas of this invention may be prepared by treating the amphoteric compound with a substantially equimolar amount of the chosen acid or base. The salt-formation step can be carried out in aqueous solution or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the solid salt is obtained. Alternatively, other recovery techniques are also applicable, such as free-drying when the solvent is water or the use of an antisolvent in the case of an organic solution, e.g., the addition of diethylether to a methanolic solution of the product will cause precipitation of the salt from said solution to occur.

The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the cyclicsulfamylureas of this invention which are basic in character are those which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydriodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, oxalate, succinate and maleate salts.

The bases which are used to prepare the pharmaceutically acceptable base salts of the cyclicsulfamylureas of this invention are those which form non-toxic salts containing pharmaceutically acceptable cations, such as the alkali metal, alkaline-earth metal, ammonium or watersoluble amine addition salts like the lower alkanolammonium and other base salts with organic amines which are compatible with the human system. Preferred members of this group include the sodium, potassium, magnesium, calcium and ethanolammonium salts. Some of these salts such as the sodium, magnesium and ethanolammonium salts are especially valuable in view of their water-solubility.

As previously mentioned, the cyclicsulfamylurea compounds of this invention are all readily adapted to therapeutic use as antidiabetic agents. Furthermore, the toxicity of all these compounds has been found to be quite low when they are orally administered to mice in amounts which are sufficient to achieve the desired therapeutic effects. Moreover, no other harmful pharmacological side effects, such as crystalluria or kidney damage, have been observed to occur as a result of their administration. The hypoglycemic activity of these particular sulfamylureas is Well illustrated by the series of tests hereinafter described, wherein intact male albino rats, each weighing approximately 150 grams, are the experimental test animals used. The test animals are fasted approximately 2024 hours prior to oral administration of the drug, and food is also withheld from them throughout the entire test period. Blood sugar levels are then determined as glucose on tail blood samples at two and four hour intervals in accordance with the micro method of Folin- Malmros, and groups of control and treated rats are sacrificed after each determination. The treated animals are given the sulfamylurea to be tested at the 100 mg./kg. dosage level; in each instance, the drug is suspended in a 1% carboxymethylcellulose solution and the doses are administered in a volume of 4 ml./ kg. In each and every case, the control rats are given the same vehicle alone, and the results obtained are expressed in terms of the percent decrease in the fasting blood glucose value from the control pretreatment value. In this connection, it is significant to note that the results obtained show that the compounds of the present invention exhibit a hypoglycemic effect which is comparable to that afforded by the known clinically useful oral antidiabetic agents in this field. Data illustrating the results of acute toxicity tests performed in conjunction with the clinical testing program indicate that the herein described cyclicsulfamylureas can all be considered to be relatively non-toxic in nature. Microscopic examination of urine samples collected five and twenty-five hours after oral administration to such animals reveals the absence of any crystalluria or kidney damage as aforementioned.

In accordance with a method of treatment of the present invention, the hypoglycemically-active cyclicsulfamylureas or one of their aforementioned pharmaceutically acceptable salts can be administered to the diabeticallyafflicted subject via the oral route as previously indicated. In general, these compounds are most satisfactorily administered at a dosage level that is in the range of from about 75 mg. to about 2.25 g. per day in the order of about one to about five doses, although variations will necessarily occur depending upon the weight of the subject being treated. However, a dosage level that is in the range of from about 1.0 mg. to about 30mg. per kg. of body weight per day is most desirably employed in order to achieve effective results. Nevertheless, it is to be appreciated that still other variations may also occur in this respect, depending upon the severity of the patients condition and on its individual response to said hypoglycemic agent, as well as on the particular oral formulation and/ or compound chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful or deleterious side effects to ensue, provided that such higher doses levels are first divided into several smaller doses that are to be administered throughout the day.

The herein described cyclicsulfamylureas or one of their aforementioned pharmaceutically acceptable salts may be administered either alone or, and preferably, in combination with a pharmaceutically acceptable carrier. Such administration can be carried out in either single or multiple doses. The compounds of this invention may be administered in suitable unit dosage forms which will preferably contain at least 1.0 mg. per dosage unit, although concentration levels in the range of from about 1.0 to about 30 mg. per unit dosage per day may be employed to advantage. When larger doses of these hypoglycemic agents are to be employed, it is preferable to administer two or more unit doses at various time intervals, adjusting, if necessary, the content of the antidiabetic agent per unit dosage form accordingly. Moreover, multiple dose treatment has indicated the feasibility, in some instances, of administering the sulfamylurea-containing compositions at periodic time intervals, e.g., by orally administering the hypoglycemic agent to an afllicted subject at a dosage level that is in the range of approximately 0.2501.0 g. per day divided into about two to about five doses of equal strength that are to be administered throughout the day. Furthermore, optimum results can often be obtained in such cases by administering a higher dose initially, followed by the administration of a maintenance dose of therapy at a lower dosage thereafter, e.g., 1.0 g. the first day, 0.6 g. the second day, 024 g. the third day, and 0.2 g. per day thereafter.

It is apparent from the foregoing that the hypoglycemically-active compounds of this invention can be administered in a wide variety of different oral dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of capsules, tablets, lozenges, troches, hard candies, aqueous suspensions, elixirs, etc. Such carriers include solid diluents or fillers, aqueous media, various non-toxic organic solvents, and the like. Moreover, these oral pharmaceutical compositions can be sweetened and/or flavored by means of various agents of the type commonly employed for just such a purpose. In general, the sulfamylureas of this invention are present in such oral dosage forms at concentration levels ranging from about 0.5% to about by weight of the total composition, i.e., in amounts which are suflicient to provide the desired unit dosage previously indicated.

For purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along with various disintegrants such as alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, gelatin and acacia; in addition, lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft elastic and hardfilled gelatin capsules; preferred materials in this connection would also include polyethylene glycol, propylene glycol and glycerin as they may not only be used in this particular type of pharmaceutical dosage form as diluents but also as plasticizing agents as well, serving to protect the capsule against leakage that might possibly occur due to the denaturation of the gelatin protein contained in the capsule wall. When aqueous suspensions and/or elixirs are desired for oral administration, the hypoglycemically-active ingredient may be combined with various sweetening and flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol and glycerin as well as various like combinations thereof.

This invention is further illustrated by the following examples, which are not to be construed in any way as imposing any limitations upon the scope thereof. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications and equivalents thereof which readily suggest themselves to those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.

Example I A suspension consisting of 930 g. (3.43 moles) of the monosodium salt of 8-sulfamyl-l-oxa-8-azaspiro[4.5]- decane and 1141 g. (3.89 moles) of 1,1-diphenyl-3- cyclohexylurea in 9.2 liters of N,N-dimethylformamide was heated on a steam bath for 22 hours while under a nitrogen atmosphere. The resulting solution was then cooled to room temperature (25 C.) and added to 24 liters of water, whereupon a white-oily solid soon separated. The latter substance was a subsequently removed by means of filtration and the filtrate extracted with three-successive 24-liter portions of diethyl ether. The aqueous layers were saved in each case, filtered and then made acidic with ca. 500 ml. of concentrated hydrochloric acid. The crystalline material which formed almost immediately was collected on a filter funnel and washed with three liters of water. After air-drying, the weight of the crude damp product amounted to 1305 g. It was then dissolved in 14 liters of methylene chloride and washed therein with three liters of cold water. Upon drying the organic layer and treating the latter with activated charcoal, there was obtained a filtrate which was subsequently concentrated in vacuo as 9 liters of ethyl acetate were simultaneously added thereto. The

mixture so obtained was then concentrated in volume to ca. 6 liters in order to completely remove the methylene chloride solvent. Crystals of the white crystalline product which had separated at this point were then removed by means of filtration and washed with ethyl acetate and diethyl ether. In this manner, there were obtained 1020 g. of 1-[N-(oxa-8-azaspiro[4.5]decane)-sulfonyl]- 3-cyclohexylurea, M.P. 185-186" C. The melting point remained constant after one recrystallization from a methylene chloride-ethyl acetate mixture.

Analysis.-Calcd. for C15H27N3O4SZ C, 52.15; H, 7.88; N, 12.16. Found: C, 52.48; H, 7.80; N, 12.18.

Example II The procedure described in Example 1 was followed using 3.63 g. (0.015 mole) of the rnonosodium salt of 8-sulfamyl-1-0xa-8-azaspiro[4.5]decane, 5.20 g. (0.017 mole) of 1,1-diphenyl-3-cycloheptylurea and 40 ml. of N,N-dimethylformamide. In this manner, there were obtained 4.5 g. of 1-[N-(l-oxa-8-azaspiro[4.5]decane)- sulfonyl]-3-cycloheptylurea, M.P. 149150 C. The melting point remained essentially the same (150-150.7 C.) after one recrystallization from benzene-diethyl ether in the presence of charcoal.

Analysis.Calcd. for C H N O S: C, 53.45; H, 8.13; N, 11.69. Found: C, 52.83; H, 7.78; N, 12.02.

Example Ill The procedure described in Example I is repeated using other starting materials and reagents in place of those specifically mentioned therein. For the sake of time and convenience and in order to avoid any unnecessary repetition of experimental detail, this general procedure is outlined below as follows:

To 0.013 mole of the sodium salt of the cyclocaminosulfonamide suspended in 20 ml. of anhydrous dimethylformamide there is added 0.016 mole of the appropriate N,N-diphenylurea derivative. The reaction mixture is then heated on a steam bath overnight for approximately 16 hours, cooled to room temperature and diluted with 125 ml. of water. After extraction of the resulting solution with diethyl ether and subsequent acidification of the aqueous layer, there is obtained the desired cyclicsulfamylurea in the form of a crystalline precipitate.

The sulfamylurea products obtained in this manner are listed below in the following Table I, which also includes their melting points and respective elementary analyses.

TABLE I Analyses Sulfamylurea M.P. C.) Calcd. Found C H N C II N l-[N-(4-methoxypiperidinc)sulfony11-3- cyclohexylurea 167-167. 5 48. 88 7. 89 13. 16 49. 08 7. 89 13. 29 1-[N-(4-methoxypiperidine)sulfonyl]-3- cyeloheptylurea 143-144 50. 43 8. 1G 12. 50. 59 8. 23 12. 45 1-[N-(4-methoxy-4-methylpiperidine) sulfonyl]-3-cyclol1eptyluroa 132-132. 5 51.85 8. 41 12.09 51. 62 8. 36 11. 96 1-[N-(3-metl10xypiperidine) sulfony cyclohexylurea. 139-140 48. 88 7. 89 13. 16 49. 27 8. 2 I-[N-(B-methoxypiperidine)sulfonyll-S- cycloheptylnrea 101-102. 5 50.43 8. 16 12.60 50.22 8.14 12. 44 1-[N-(2, 2-pentamethylenethiamorpholine) snlfonyl]-3-cyclohoptylurea 147-150 52. 41 8. 02 10. 79 52. 56 7. 10. 66 1-[N-(2, 2-pontamethylenethiamorpholine) sultonyl]-3-oyclohexylurea 158. 5-160. 5 51. 17 7. 78 11.19 51.03 7. 67 10.96 l-N-(1-oxo-2,2-pentarnethylenethiamorpholine)sulfonyl]-3-cycloheptylurea 202-204 50. 34 7. 71 10.36 50. 0G 7. 52 10. 02 l-[N -(1-0x0-2,2-11entamethylenethiarnorpholine)sulfonyl]-3-cyclohexylurea 210-212 49. 08 7. 47 10.73 48. 77 7. 12 10. 44 l-[N -(1,l-dioxo-2,2-pentamethylenethiamoi'pholine)sulfonyl]-3-cycloheptylurea 201-202 48. 43 7. 41 9. 97 48. 78 7. 41 9. 89 1-[N-(4-rnethallyloxy-4-rnethylpiperidine) sulfonyl]-3-cyclohexylurea 147-149 54. 66 8. 37 11. 25 54. 57 8. 58 10.90 1-[N-(4-methallyloxy-4-methylpiperidine) sulfonyl]-3-eycloheptylurea -111 55. 79 8. 58 10.84 56. O8 9. 04 10. 40 1-[N-(4-methoxyethoxy-4-methylpiperi- (line)sulionyH-B-cyclohexylurca -171 50. 90 8. 28 11. 13 50. 63 7. 96 1-[N-(4-rnethoxycthoxy-4-methylpiperidine)sulfonyl]-3cycloheptylurea 134-135 52. 15 8. 49 10. 73 51. 90 8. 70 l-[N- (4,4-etl1ylcnedioxypiperidine) sulfonyl]-3-cyclohcptylurea 153-155 49. 84 7. 53 11. 63 50. 38 7. 69 11. 27 1-[N-(4,4-ethylenedioxypiperidine) TABLE I-Camtinued Analyses Sulfamylurea M.P. C.) Calcd. Found C H N O H N sulfonyl]-3-(bicycle[2.2.11hept-5-ene-2-y1- ylmethyDurea 91-93 51. 45 7. 29 11.25 51. 50 7. 35 11.09 l-[N-(4,4-1sopropylenedloxyplperidine) sulfonyl]-3-cyelohexylurea 191-192 49. 84 7.53 11.63 49.89 7. 53 11.28 l-[N-(4,4-1sopropy1enedioxypiperidine) sulfonyl]-B-cyeloheptylurea 150-151 51.18 7. 79 11. 19 51. 32 7. 91 10.94 l-[N-(4,4-1s0propylenedioxypiperidine) ylruethyDurea 134-135 53. 50 7. 09 13.14 53. 32 6. 82 12.05 l-[N-(4,4-1sopropylenedioxypiperidine) ylmethyDurea 131-132 52. 69 7. 54 10. 85 52. 83 7. 54 10. 94 1-[I I-(4,4-(flfi-dimethyl) propylenedioxyplperidine)sulfonyl]-3-eyclohexylurea 218-219 52.42 8.02 10. 79 52. 54 7.99 10.76 1-[N-(4,4-(/S,Bdimethyl)propylenedioxypiperidine)sulfonyl]-3-cyc1ohepty1urea 187-188 53. 57 8. 24 10. 41 53. 37 8. 10. 62 1-[l I-(4,4-(B,fi-dimethy1)propylenedioxyhept-5-ene-2-ylmethyl) urea 158-159 55. 18 7. 56 10. 16 55. 28 7- 74 9. 83

Example IV A solution consisting of 3.2 g. (0.036 mole) of cyclohexyl isocyanate dissolved in 12 ml. of anhydrous dimethylforrnarnide was added to a chilled suspension of 6.6 g. (0.030 mole) of 8-sulfamly-l-oxa-8-azaspiro[4.5]- decane in ml. of anhydrous triethylamine. The reaction mixture was then stirred at room temperature for approximately 16 hours, and finally poured slowly into 500 ml. of chilled 50% aqueous acetic acid during the course of a one-half hour period with constant agitation being maintained throughout this step. The solid material which precipitated from the solution at this point was recovered by means of filtration and subsequently washed with cold water. The product so obtained was then dissolved in 5% aqueous sodium carbonate and the resulting aqueous solution was immediately filtered. Isolation of the desired compound from said solution was then effected by slowly pouring the filtrate into 500 ml. of chilled 20% aqueous acetic acid, whereupon precipitation of the crystalline material occurred. The precipitate was then filtered, washed Well with cold water and subsequently air-dried to constant weight. In this manner, there was obtained 1-[N-(1-oxa-8-azaspiro[4.5]decane)sulfonyl]-3- cyclohexylurea, M.P. 183.5-184.5 C.

Example V The procedures described in Examples I-III (method A) and IV (method B) are again repeated using still other starting materials and reagents to prepare additional cyclicsulfamylureas not reported in Example III. The compounds obtained in this manner are listed below as follows:

1-[N- (4-allylpropoxypiperidine sulfonyl] -3-cyclopentylurea 1- [N-(4-methallylethoxypiperidine sulfonyl] -3- ([3- phenylethyl) urea 1- N- (4-trifluoromethoxypiperidine) sulfonyl] -3- (p-dimethylaminophenyl) urea 1- [N 4-trifluoroethoxypiperidine sulfonyl] -3- n-octyl) urea 1- [N- (4-trifluoropropoxypiperidine sulfonyl] -3 -cyclobutylmethylurea 1- [N-(4-cycloethoxypiperidine) sulfonyl] -3-cyc1ohexylurea 1- [N- (4-cyclopropoxypiperidine sulfonyl] -3 -cyclopropylurea 1- [N- (4-cyclobutoxypiperidine) sulfonyl] -3- (m-xylyl) urea 1- [N-(4-cyclohexoxypiperidine sulfonyl] -3- [:p- (S- methylmercaptophenyl) urea 1- [N- (4-methoxy-4-methylpiperidine) sulfonyl] -3- ethylurea 1- [N- (4-n-propoxy-4-ethylpiperidine sulfonyl] -3- cycloheptylurea 1- [N- (4-ethoxy-4-n-butylpiperidine) sulfonyl] -3-cyclohexylethylurea 1- [N- (4-methoxyethoxy-4-n-propylpiperidine) sulfonyl] 3-cyclobutylurea 1- [N- (4-allylmeth0xy-4-n-butylpiperidine) sulfonyl] -3- (p-chlorobenzohydryl) urea 1- [N- (4-trifluoroethoxy-4-methylpiperidine sulfonyl] -3- (n-propyl) urea 1- [N- 4-trifiuoroethoxy-4-ethyl pip eridine) sulfonyl] -3 (p-chlorophenyl) urea 1-[N-(4-trifluoroethoxy-4 n-propylpiperidine) sulfonyl] 3 -cyclohexylurea 1- [N- (4-cyclopropoxy-4-methylpiperidine) sulfonyl] -3 (p-dimethylaminophenyl) urea 1- [N- (4-methoxy-4-vinylpiperidine sulfonyl] -3-cyc1opentylmethylurea 1- [N-(4-n-pr-opoxy-4-allylpiperidine) sulfonyl] -3- cycl oheptylurea 1- [N- (4-ethoxy-4-cyclobutylpiperidine sulfonyl] -3- isoamylurea 1- N-(4-methoxyethoxy-4-cyclopentylpiperidine) sulfonyl] -3 -cyclohexylurea 1- [N- (4-allylmethoxy-4-cyclopropylpiperidine) sulfonyl] 3- (fl-phenylethyl) urea 1- N- (4-trifluoropropoxy-4-cyc1obutylpiperidine sulfonyl] -3 -cyclopropylurea l- [N- (4-trifiuoroethyl-4-n-propoxypiperidine sulfonyl] 3-(bicyclo [2.2.1 hept-5-ene-2-ylmethyl) urea 1- [N 3 ,4-ethylenedioxypiperidine) sulfonyl] -3- (bicyclo [2.2.1] hept-2-ylmethyl) urea 1- [N- 3 ,4-di-n-propoxypyrrolidine sulfonyl] -3 (bicyclo [2.2. 1 hept-5-ene-2-ylmethyl) urea 1- [N 3 ,4-ethylenedioxypiperidine) sulfonyl] -3 (bicyclo [2.2.1]hept-2-ylmethyl)urea 1- [N- 3,4-dimethoxypiperidine) sulfonyl] -3 (bicyclo [2.2. 1 hept-5-ene-2-ylmethyl urea 1- [N-( l-oxa-8-azaspiro [4.5 decane) sulfonyl] -3 (bicyclo [2.2.1] hept-5-ene-2-ylmethyl)urea 1- [N- 3-n-butoxypiperidine sulfonyl] -3 (bicyclo 2.2.1]

hept-2-ylmethyl urea In the case of method B, the general procedure employed is outlined below as follows:

To 0.03 mole of the cyclicaminosulfonamide dissolved in 18 ml. of anhydrous triethylamine there is added 0.036 mole of the appropriate isocyanate dissolved in 12 ml. of anhydrous dimethylformamide. The reaction mixture is allowed to stir at room temperature for approximately 16 hours (overnight) and then diluted with 150 ml. of water. Isolation of the desired product from said aqueous solution is then achieved in the same manner as that described in method A. Alternatively, the product may also be isolated from the stirred reaction mixture by employing the procedure described in Example III, where in it is first slowly poured into 500 ml. of 20% aqueous glacial acetic acid and worked up in the manner described therein.

Example VI A cyclicsulfamylurea is dissolved in an equimolar amount of a aqueous sodium hydroxide solution at a temperature of approximately 40 C. The resulting solution is then adjusted to a pH of 7.5 by the addition of small amounts of either the sulfamylurea or 15% aqueous sodium hydroxide solution as the case may be. The so-adjusted solution is then filtered and allowed to stand for some time in an ice-box until crystallization of the desired salt occurs, e.g., the sodium salt of 1-[N-(1- oxa-S-azaspiro 4.5 decane sulfonyl] -3-cyclohexylurea if the latter compound is the particular sulfonylurea employed as starting material in this example.

In like manner, the use of lithium hydroxide in place of the sodium hydroxide employed above affords the corresponding lithium salts.

Example VII The procedure described in Example VI is initially followed except that the concentration of the aqueous sodium hydroxide employed is such that it is sufiicient to afiord a solution of the sulfamylurea compound. This solution is then heated to 80 C. and filtered, and the resulting filtrate treated with twice the equimolar amount of a 15 aqueous potassium carbonate solution at this same temperature. After cooling the resultant reaction mixture to room temperature, crystallization of the so prepared potassium salt of the particular sulfamylurea employed as starting material soon occurs.

Example VIII A cyclicsulfamylurea prepared as described in Examples I-V is dissolved in an equimolar amount of triethanolamine and sufficient water to afford a 50% solution of said sulfamylurea. This solution is then heated to approximately 60 C., filtered while hot and the resulting filtrate poured into an aqueous calcium chloride solution containing 100 g. of calcium chloride dissolved in 100 ml. of water and whose temperature is also at 50 C. On cooling to room temperature and further standing for several hours, the calcium salt of the particular sulfamylurea employed as starting material crystallizes from solution. In this way, the calcium salt .of 1-[N-(1-oxa-8- azaspiro [4.5] decane -sulfonyl] -3-cycloheptylurea is obtained when the latter sulfamylurea is the particular compound employed as starting material.

In like manner, the strontium and barium salts of each of the cyclicsulfamylureas of this invention are also each individually obtained in accordance with this very same reaction procedure by merely substituting the appropriate alkaline-earth metal chloride, i.e., either strontium chloride or barium chloride as the case may be, in place of the calcium chloride used above.

Example IX A cyclicsulfamylurea prepared as described in Examples I-V is dissolved in 2 ml. of 10 N ammonium hydroxide at 50 C. The resulting solution is filtered immediately, and then allowed to cool to room temperature and to further stand at this point for several hours until crystallization occurs. In this manner, white crystals of the ammonium salt of 1-[N-(2,2-pentamethylenemorpholine) sulfonyl]-3-cycloheptylurea are obtained from solution as a crystalline precipitate when said sulfamylurea is the particular starting material employed in this example.

Example X Equimolar amounts of a cycli-csulfamylurea such as that used in Example IX and monoethanolamine are dissolved in a sutficient amount of water at 58 C. to afford a 20% solution of the free sulfamylurea compound. Upon evaporation of the so prepared aqueous solution under reduced pressure at 40 C., there is obtained a solid residual material which is the mon oethanolammonium salt of the desired compound.

In like manner, each of the other cycliosulfamylureas of this invention individually form salts with diethanolamine, triethanolamine, ethylene diamine, diethylamine, triethylamine and pyridine by contacting one of the aforesaid sulfamylureas with the appropriate lower alkanolamine or lower alkylamine as the case may be in accordance with this very same reaction procedure.

Example XI The non-toxic acid addition salts of the amphoteric cyclicsulfamylureas of this invention are prepared by either one of two general methods. In the case of the hydrohalide salts, such as the hydrochloride, hydrobromide and hydriodide, this is accomplished by first dissolving the amphoteric sulfamylurea compound in absolute alcohol (ethanol) followed by the introduction of the appropriate hydrogen halide gas into the solution until saturation of said solution with respect to the 'gas is complete, whereupon the desired salt precipitates from solution. The crystalline product so obtained is then recrystallized from acetone to yield the pure hydrohalide salt. In this manner, equimolar amounts of 1-[N-(1oxa- 8 azaspiro [4.5]decane)sulfonyl] 3 (p dimethylaminophenyl)urea and hydrogen chloride react to form the corresponding acid addition salt.

In the case of the corresponding nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, oxalate, succinate, maleate, gluconate and saccharate salts, the respective acid and the amphoteric sulfamylurea are both separately dissolved in ethanol and the two solutions are then mixed, followed by the addition of diethyl ether to the resulting reaction mixture in order to effect precipitation of the desired acid addition salt from said solution.

Example XII A dry solid pharmaceutical composition is prepared by blending the following materials together in the :proportions by weight specified below:

1 [N 1 oxa-8-azaspiro[4,5]decane)-sulfonyl]-3- gnesium s earate =5 5 1 7 After the dried composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet being of such size that it contain 100 mg. of the active ingredient.

Example XIII A dry solid pharmaceutical composition is prepared by combining the following materials in the proportions by weight specified below:

1 [N 1 oxa-8-azaspiro[4,5]decane)-sulfonyl]-3- cycloheptylurea 50 Calcium carbonate 20 Polyethylene glycol (average molecular weight, 4000) 30 Example XIV A dilute aqueous-levulose solution of the calcium salt of 1 [N 4-methoxypiperdine)sulfonyl]-3-cycloheptylurea (prepared as described in Example VIII for the corresponding 1-oxa-8-azaspiro[4.5 ]decane compound) is prepared by dissolving said salt in a 50% aqueous levulose solution in such amount that each ml. of solution contains 75 mg. of the sulfamylurea calculated on the basis of its free sulfamylurea form. The so obtained solution can then be sweetened and/ or flavored as desired in order to mask the taste of the essential active ingredient therein, and rendered more viscous by the addition of the appropriate amount of methyl cellulose.

Example XV A dry solid pharmaceutical composition is prepared by blending the followin materials together in the portions by weight specified below:

1 [N (4-methoxy-4-methylpiperdine)-su1fonyl]-3- After the dried composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet being of such size that it contains 100 mg. of the active ingredient.

Example XVI A mixture consisting of 2.73 g. (0.0112 mole) of the monosodium salt of 4,4-ethylenedioxypiperidinesulfonamide (i.e., 1,4-dioxa-8-azaspiro[4.5]decane-8-sulfonamide sodium salt), 3.92 g. (0.0123 mole) of 1,1-diphenyl-3- cyclohexylurea and 25 ml. of N,N-dimethylformamide Was heated on a steam bath overnight (-16 hours) while being subjected to constant agitation (provided by a magnetic stirrer) under a nitrogen atmosphere. The mixture was then cooled and poured into 150 ml. of water, and the resulting aqueous solution subsequently washed two times with diethyl ether. Upon acidification of the washed aqueous solution to a Congo red end point (solution made acid to Congo red paper) with concentrated hydrochloric acid followed by cooling in an ice bath (for 30 minutes), there was obtained a crystalline precipitate which was subsequently filtered and airdried to constant weight. In this way, there was obtained a 1.49 g. (38%) yield of 1 [N-4,4-ethylenedioxypiperdine)sulfonyl]-3- cyclohexylurea, M.P. 176-177" C.

Analysis.Calcd. for C H N O S: C, 48.39; H, 7.25; N, 12.09; S, 9.23. Found: C, 48.45; H, 7.37; N, 11.83; S, 9.29.

18 What is claimed is: 1. A compound selected from the group consisting of A. Those of the formula HO NHCONHR' wherein (a) R'" is a member selected from the group consisting of alkyl of two to about eight carbon atoms, cycloalkyl-alkyl of from four to about nine carbon atoms, cycloalkyl of three to about eight carbon atoms, bicyclo-[2.2.1]hept-5-ene-2- ylmethyl, bicyclo [2.2.1]hept-2-ylmethy, aralkyl of seven to about thirteen carbon atoms, p-chlorophenyl, p-di(lower alkyD-aminophenyl and S-(lower alkyl)mercaptophenyl; and

(b) Z represents a radical selected from the group consisting of wherein R is a member chosen from the group consisting of hydrogen, lower alkyl, trifluoroethyl, lower alkenyl, cycloalkyl of up to six carbon atoms and cycloalkenyl of up to six carbon atoms; R is a member chosen from the group consisting of lower alkoxy, lower alkoxylower alkoxy, lower alkenyl-lower alkoxy, lower polyfluoroalkoxy and cycloalkoxy of up to six carbon atoms; and when R and R are taken together, they form a radical selected from the group consisting of CH CH CH O,

SCH CH O, -CH CH OCH -CH CH CH CH O, CH CH OCH CH O-, CH CH CH S, -CH CH CH NH and wherein R is lower alkyl;

where X is a member chosen from the group consisting of oxygen, sulfur, l-oxosulfur and 1,1- dioxosulfur, and m is an integer of from four to five;

RzO-CHOH2 N R3OOH-(CH2)x wherein R and R are each lower alkyl, and x is an integer from one to two; and

wherein x is an integer from one to two; and

wherein G is a member chosen from the group consisting of CH1 CHzCHa-, -CH2-CH- and (7H3 -CHz-CCHz-;

B. The alkali metal salts of A C. The alkaline earth metal salts of A D. The ammonium addition salts of A E. The amine addition salts of A, and

F. The acid addition salts of A wherein R' is p-di(lower alkyl) aminophenyl.

2. 1 [N (4+methoxypiperidine)sulfonyl1-3-cycloheptylurea.

3. 1 [N (4-methoxy-4-methylpiperidine)sulfonyl]-3- cycloheptylurea.

4. 1 [N (3 hexylurea.

5. 1 [N (1-oxa-8-azaspiro[4.5]decane)sulfonyl]-3- cyclohexylurea.

6. 1 [N cyclohexylurea.

7. 1 [N (4,4 ethylenedioxypiperidine)sulfonyl]-3- (bicyclo[2.2.1]hept-5-ene-2-ylmethyl)urea.

8. A compound of claim 1 wherein Z is a radical of the formula wherein R is a member chosen from the group consisting of hydrogen, lower alkyl, trifiuoroethyl, lower alkenyl, cycloalkyl of up to six carbon atoms and cycloalkenyl of up to six carbon atoms; R is a member chosen from the group consisting of lower alkoxy, lower alkoxy-lower alkoxy, lower alkenyl-lower alkoxy, lower polyfiuoroalkoxy and cycloalkoxy of up to six carbon atoms; and when R and R are taken together, they form a radical selected from the group consisting of -CH CH CH O, SCH CI-I O-, -CH CH OCH CH CH CH CH O-, -CH CH OCH CH O, -CH CH2cH2S, and -CH CH CH CH NH 9. A compound of claim 1 wherein Z is a radical of the formula wherein R is lower alkyl.

10. A compound of claim 1 wherein Z is a radical of the formula methoxypiperidine) sulfonyl] -3-cyclo- (4,4-ethylenedioxypiperidine sulfonly] -3 20 wherein X is a member chosen from the group consisting of oxygen, sulfur, l-oxosulfur and l,1-dioxosulfur, and m is an integer of from four to five.

11. A compound of claim 1 wherein Z is a radical of the formula R2O-CHCH IhO-CH-(CHz);

wherein R and R are each lower alkyl, and x is an integer from one to two.

12. A compound of claim 1 wherein Z is a radical of the formula wherein x is an integer from one to two.

13. A compound of claim 1 wherein Z is a radical of the formula wherein G is a member chosen from the group consisting of References Cited by the Examiner UNITED STATES PATENTS JOHN D. RANDOLPH, Primary Examiner.

IRVING MARCUS, WALTER A. MODANCE,

Examiners.

EGON E. BERG, Assistant Examiner, 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A. THOSE OF THE FROMULA 